CASK Disorders; CASK Related Intellectual Disability; CASK Related Syndrome; MICPCH Syndrome; Microcephaly with Pontine and Cerebellar Hypoplasia; X-linked Intellectual Disability XL-ID with or without Nystagmus

CASK-related gene disorders are a group of disorders affecting brain development that are caused by mutations in the CASK gene. There are two main forms:

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  Microcephaly with pontine and cerebellar hypoplasia (MICPCH), and

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  X-linked intellectual disability (XL-ID) with or without nystagmus.

CASK-related gene disorders are more commonly reported in females and include a spectrum of phenotypes that differs in females and males:

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  Females typically have moderate-to-severe intellectual disability, and most have progressive MICPCH. Possible findings are ophthalmologic anomalies and sensorineural hearing loss. Females who are related to males with the XL-ID nystagmus phenotype may rarely present with a mild-to-severe intellectual disability phenotype.

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  The spectrum in males is broad, ranging from mild XL-ID with nystagmus and additional clinical features to severe intellectual disability, MICPCH, early infantile epilepsy, and early myoclonic epilepsy.

Diagnostic testing: The diagnosis of CASK-related gene disorders is made by:

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  Molecular genetic testing for CASK gene mutations;

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  Electroencephalogram (EEG) testing;

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  Computed tomography (CT)/magnetic resonance imaging (MRI);

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  Use of multi-gene panel; or

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  Genomic testing.

Physical findings:

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  Progressive microcephaly (small head size);

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  Pontine hypoplasia (underdevelopment of the pons and cerebellum of the brain);

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  Cerebellar hypoplasia (underdevelopment of the part of the brain that controls balance and coordination);

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  Hypotonia (low muscle tone);

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  Hypertonia (stiff, rigid muscles and resistance to movement);

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  Seizures;

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  Nystagmus (rapid, uncontrollable rhythmic eye movement);

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  Strabismus (eyes that look in different directions);

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  Optic nerve hypoplasia (underdevelopment of one or both optic nerves causing vision impairment ranging from mild to blindness);

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  Retinopathy (non-inflammatory diseases of the retina);

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  Sensorineural hearing loss; and

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  Short stature.

ICD-9: 758.9

ICD-10: Q04.3

CASK-related gene disorders are present at birth with symptoms lasting throughout the lifetime of the individual. These disorders present with a spectrum of symptoms ranging from mild to severe.

Individuals with MICPCH usually have severe intellectual disability. They may have sleep disturbances and exhibit self-biting, hand flapping, or other abnormal repetitive behaviors. Seizures are also common in this form of the disorder.

XL-ID with or without nystagmus (rapid, involuntary eye movements) is a milder form of CASK-related intellectual disability. The intellectual disability in this form of the disorder can range from mild to severe; some affected females have normal intelligence. About half of affected individuals have nystagmus. Seizures and rhythmic shaking (tremors) may also occur in this form.

The prognosis for individuals with CASK-related gene disorders varies depending on the areas of the brain affected by the gene mutation. Degrees of cognitive impairment or intellectual disability are lifelong.

There is no cure for CASK-related gene disorders. Treatment is symptomatic and includes standard management of developmental delay and intellectual disability issues; medication for seizures; nutritional support; use of physiotherapy; and treatment of abnormal vision or hearing loss.

Suggested MER for Evaluation:

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  Clinical history and examination that describes the diagnostic features of the impairment;

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  EEG with evidence of burst suppression pattern;

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  Imaging studies such as CT or MRI;

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  Reports of genetic testing; and

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  Metabolic laboratory studies.

Suggested Listings for Evaluation:

11.02

12.05

12.11

110.08

111.02

111.09

112.05

112.11

112.14

11.07